Low expression of the metabolism-related gene SLC25A21 predicts unfavourable prognosis in patients with acute myeloid leukaemia
Acute myeloid leukaemia (AML) is a heterogeneous disease associated with poor outcomes. To identify AML-specific genes with prognostic value, we analysed transcriptome and clinical information from The Cancer Genome Atlas (TCGA) database, Gene Expression Omnibus (GEO) datasets, and Genotype-Tissue E...
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2022.970316/full |
| _version_ | 1797997837178372096 |
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| author | Wenjun Wang Qian Liang Jingyu Zhao Hong Pan Zhen Gao Liwei Fang Yuan Zhou Jun Shi |
| author_facet | Wenjun Wang Qian Liang Jingyu Zhao Hong Pan Zhen Gao Liwei Fang Yuan Zhou Jun Shi |
| author_sort | Wenjun Wang |
| collection | DOAJ |
| description | Acute myeloid leukaemia (AML) is a heterogeneous disease associated with poor outcomes. To identify AML-specific genes with prognostic value, we analysed transcriptome and clinical information from The Cancer Genome Atlas (TCGA) database, Gene Expression Omnibus (GEO) datasets, and Genotype-Tissue Expression (GTEx) project. The metabolism-related gene, SLC25A21 was found to be significantly downregulated in AML, and was associated with high white blood cell (WBC) counts, high pretrial blood (PB) and bone marrow (BM) blast abundance, FLT3 mutation, NPM1 mutation, and death events (all p value <0.05). We validated the expression of SLC25A21 in our clinical cohort, and found that SLC25A21 was downregulated in AML. Moreover, we identified low expression of SLC25A21 as an independent prognostic factor by univariate Cox regression (hazard ratio [HR]: 0.550; 95% Confidence interval [CI]: 0.358–0.845; p value = 0.006) and multivariate Cox regression analysis (HR: 0.341; 95% CI: 0.209–0.557; p value <0.05). A survival prediction nomogram was established with a C-index of 0.735, which indicated reliable prognostic prediction. Subsequently, based on the median SLC25A21 expression level, patients in the TCGA-LAML cohort were divided into low- and high-expression groups. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of DEGs highlighted growth factor binding, extracellular structure organization, cytokine‒cytokine receptor interaction, etc. The results of gene set enrichment analysis (GSEA) indicated that the epithelial-mesenchymal transition, KRAS signalling, oxidative phosphorylation, and reactive oxygen species pathways were enriched. Through gene coexpression and protein‒protein interaction (PPI) network analysis, we identified two hub genes, EGFR and COL1A2, which were linked to worse clinical outcomes. Furthermore, we found that lower SLC25A21 expression was closely associated with a significant reduction in the levels of infiltrating immune cells, which might be associated with immune escape of AML cells. A similar trend was observed for the expression of checkpoint genes (CTLA4, LAG3, TIGIT, and HAVCR2). Finally, drug sensitivity testing suggested that the low-expression SLC25A21 group is sensitive to doxorubicin, mitomycin C, linifanib but resistant to JQ1, belinostat, and dasatinib. Hence, our study demonstrated that a low expression level of SLC25A21 predicts an unfavourable prognosis in patients with AML. |
| first_indexed | 2024-04-11T10:39:08Z |
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| spelling | doaj.art-8e66c90d50864d608c2953b829dfe2d72022-12-22T04:29:13ZengFrontiers Media S.A.Frontiers in Genetics1664-80212022-09-011310.3389/fgene.2022.970316970316Low expression of the metabolism-related gene SLC25A21 predicts unfavourable prognosis in patients with acute myeloid leukaemiaWenjun WangQian LiangJingyu ZhaoHong PanZhen GaoLiwei FangYuan ZhouJun ShiAcute myeloid leukaemia (AML) is a heterogeneous disease associated with poor outcomes. To identify AML-specific genes with prognostic value, we analysed transcriptome and clinical information from The Cancer Genome Atlas (TCGA) database, Gene Expression Omnibus (GEO) datasets, and Genotype-Tissue Expression (GTEx) project. The metabolism-related gene, SLC25A21 was found to be significantly downregulated in AML, and was associated with high white blood cell (WBC) counts, high pretrial blood (PB) and bone marrow (BM) blast abundance, FLT3 mutation, NPM1 mutation, and death events (all p value <0.05). We validated the expression of SLC25A21 in our clinical cohort, and found that SLC25A21 was downregulated in AML. Moreover, we identified low expression of SLC25A21 as an independent prognostic factor by univariate Cox regression (hazard ratio [HR]: 0.550; 95% Confidence interval [CI]: 0.358–0.845; p value = 0.006) and multivariate Cox regression analysis (HR: 0.341; 95% CI: 0.209–0.557; p value <0.05). A survival prediction nomogram was established with a C-index of 0.735, which indicated reliable prognostic prediction. Subsequently, based on the median SLC25A21 expression level, patients in the TCGA-LAML cohort were divided into low- and high-expression groups. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of DEGs highlighted growth factor binding, extracellular structure organization, cytokine‒cytokine receptor interaction, etc. The results of gene set enrichment analysis (GSEA) indicated that the epithelial-mesenchymal transition, KRAS signalling, oxidative phosphorylation, and reactive oxygen species pathways were enriched. Through gene coexpression and protein‒protein interaction (PPI) network analysis, we identified two hub genes, EGFR and COL1A2, which were linked to worse clinical outcomes. Furthermore, we found that lower SLC25A21 expression was closely associated with a significant reduction in the levels of infiltrating immune cells, which might be associated with immune escape of AML cells. A similar trend was observed for the expression of checkpoint genes (CTLA4, LAG3, TIGIT, and HAVCR2). Finally, drug sensitivity testing suggested that the low-expression SLC25A21 group is sensitive to doxorubicin, mitomycin C, linifanib but resistant to JQ1, belinostat, and dasatinib. Hence, our study demonstrated that a low expression level of SLC25A21 predicts an unfavourable prognosis in patients with AML.https://www.frontiersin.org/articles/10.3389/fgene.2022.970316/fullSLC25A21prognosisbioinformaticsGEOTCGAimmune checkpoint |
| spellingShingle | Wenjun Wang Qian Liang Jingyu Zhao Hong Pan Zhen Gao Liwei Fang Yuan Zhou Jun Shi Low expression of the metabolism-related gene SLC25A21 predicts unfavourable prognosis in patients with acute myeloid leukaemia Frontiers in Genetics SLC25A21 prognosis bioinformatics GEO TCGA immune checkpoint |
| title | Low expression of the metabolism-related gene SLC25A21 predicts unfavourable prognosis in patients with acute myeloid leukaemia |
| title_full | Low expression of the metabolism-related gene SLC25A21 predicts unfavourable prognosis in patients with acute myeloid leukaemia |
| title_fullStr | Low expression of the metabolism-related gene SLC25A21 predicts unfavourable prognosis in patients with acute myeloid leukaemia |
| title_full_unstemmed | Low expression of the metabolism-related gene SLC25A21 predicts unfavourable prognosis in patients with acute myeloid leukaemia |
| title_short | Low expression of the metabolism-related gene SLC25A21 predicts unfavourable prognosis in patients with acute myeloid leukaemia |
| title_sort | low expression of the metabolism related gene slc25a21 predicts unfavourable prognosis in patients with acute myeloid leukaemia |
| topic | SLC25A21 prognosis bioinformatics GEO TCGA immune checkpoint |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2022.970316/full |
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